Mycobacterium tuberculosis (Mtb) is an important human pathogen and the available data demonstrate the importance of CD4 T cells in establishing a response that restricts Mtb growth. In mice, high numbers of IFN-gamma producing Mtb-reactive CD4 T cells are first detectable at day 21 post infection and are maintained thereafter. Even so, these cells are unable to mediate Mtb elimination. We will study the T cell response to Mtb using Mtb-specific CD4 TCR tg mice. The first question that we will address is why it takes 21 days before protective T cell populations are established. We favor the view that antigen presentation during this period does not lead to the generation of protective IFN-gamma producing cells but instead to inhibitory Mtb-specific regulatory T cells. In the third AIM of this proposal we will determine if effector or memory Mtb-specific T cell populations can protect animals from Mtb infection and limit Mtb growth. Taken together our studies will provide a framework for understanding the T cell response to Mtb and they will provide the foundation for the potential exploitation of CD4 T cells in the protection and treatment of Mtb infection. Infection with Mycobacterium tuberculosis accounts for at least 1.5 million deaths per year. The experiments proposed here will answer fundamental questions regarding the adaptive immune response to Mtb infection and our findings should have direct relevance to vaccination and human disease.